Triazolyl Derivatives of Azabicyclo [3.1.0] Hexane as Dopamine D3 Receptor Modulators

ABSTRACT

The present invention relates to novel compounds of formula (IC) or a salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein:
 
p is an integer ranging from 0 to 4;
 
R 1  is independently selected from a group consisting of: halogen, hydroxy, cyano, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, C 1-4 alkanoyl or SF 5 ; or corresponds to a group R 5 ;
 
m 1 , m 2 , m 3 , and m 4  are 0;
 
m 5 , m 6  and m 7  are each independently 0, 1 or 2 wherein the sum of m 5 , m 6  and m 7  is 1 or 2;
 
R 6  is C 1-6 alkyl;
 
R 7  is halogen, C 1-6 alkyl or haloC 1-6 alkyl;
 
R 2  is hydrogen or C 1-4 alkyl;
 
n is 2 or 3;
 
X is S or —CH 2 —;
 
R 3  is C 1-4 alkyl;
 
R 4  is hydrogen, or a phenyl group, a heterocyclyl group, a 5- or 6-membered heteroaromatic group, or a 8- to 11-membered bicyclic group, any of which groups is optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of: halogen, cyano, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkanoyl;
 
R 5  is isoxazolyl, —CH 2 —N-pyrrolyl, 1,1-dioxido-2-isothiazolidinyl, thienyl, thiazolyl, pyridyl or 2-pyrrolidinonyl, wherein each group is optionally substituted by one or two substituents selected from: halogen, cyano, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkanoyl;
 
with the proviso that when m 5 =m 6   =1 , R 7  is not chlorine;
 
processes for their preparation, intermediates used in these processes, pharmaceutical compositions containing them and their use in therapy, as modulators of dopamine D 3  receptors, e.g. to treat substance related disorders, as antipsychotic agents, premature ejaculation or cognition impairment.

The present invention relates to novel compounds, processes for theirpreparation, intermediates used in these processes, pharmaceuticalcompositions containing them and their use in therapy, as modulators ofdopamine D₃ receptors.

WO 2002/40471 (SmithKline Beecham) discloses certain benzazepinecompounds having activity at the dopamine D₃ receptor.

Recently a patent application has been published as WO2005/080382 anddiscloses the following compounds of formula (I) or a salt thereof:

wherein

-   -   G is selected from a group consisting of: phenyl, pyridyl,        benzothiazolyl, indazolyl;    -   p is an integer ranging from 0 to 5;    -   R₁ is independently selected from a group consisting of:        halogen, hydroxy, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,        haloC₁₋₄alkoxy, C₁₋₄alkanoyl; or corresponds to a group R₅;    -   R₂ is hydrogen or C₁₋₄alkyl;    -   R₃ is C₁₋₄alkyl;    -   R₄ is hydrogen, or a phenyl group, a heterocyclyl group, a 5- or        6-membered heteroaromatic group, or a 8- to 11-membered bicyclic        group, any of which groups is optionally substituted by 1, 2, 3        or 4 substituents selected from the group consisting of:        halogen, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,        C₁₋₄alkanoyl;    -   R₅ is a moiety selected from the group consisting of:        isoxazolyl, —CH₂—N-pyrrolyl, 1,1-dioxido-2-isothiazolidinyl,        thienyl, thiazolyl, pyridyl, 2-pyrrolidinonyl, and such a group        is optionally substituted by one or two substituents selected        from: halogen, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,        C₁₋₄alkanoyl;        and when R₁ is chlorine and p is 1, such R₁ is not present in        the ortho position with respect to the linking bond to the rest        of the molecule; and when R₁ corresponds to R₅, p is 1.

A new class of compounds which have affinity for dopamine receptors, inparticular the dopamine D₃ receptor has been found. These compounds havepotential in the treatment of conditions wherein modulation, especiallyantagonism/inhibition, of the D₃ receptor is beneficial, e.g. to treatdrug dependency or as antipsychotic agents.

The present invention provides a compound of formula (I) or a saltthereof:

wherein:p is an integer ranging from 0 to 4;R₁ is independently selected from a group consisting of: halogen,hydroxy, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy,C₁₋₄alkanoyl or SF₅; or corresponds to a group R₅;m₁, m₂, m₃, m₄, m₅, m₆ and m₇ are each independently 0, 1 or 2 whereinthe sum of m₁,m₂, m₃, m₄, m₅, m₆ and m₇ is 1 or 2;R₆ is C₁₋₆alkyl;R₇ is halogen, C₁₋₆alkyl or haloC₁₋₆alkyl;R₂ is hydrogen or C₁₋₄alkyl;n is 2 or 3;

X is S or —CH₂—;

R₃ is C₁₋₄alkyl;R₄ is hydrogen, or a phenyl group, a heterocyclyl group, a 5- or6-membered heteroaromatic group, or a 8- to 11-membered bicyclic group,any of which groups is optionally substituted by 1, 2, 3 or 4substituents selected from the group consisting of: halogen, cyano,C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy and C₁₋₄alkanoyl;R₅ is isoxazolyl, —CH₂—N-pyrrolyl, 1,1-dioxido-2-isothiazolidinyl,thienyl, thiazolyl, pyridyl or 2-pyrrolidinonyl, wherein each group isoptionally substituted by one or two substituents selected from:halogen, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy and C₁₋₄alkanoyl;With the proviso that when m5=m6=1, R₇ is not chlorine.

In another embodiment, the present invention provides a compound offormula (IC) or a salt thereof:

wherein:p is an integer ranging from 0 to 4;R₁ is independently selected from a group consisting of: halogen,hydroxy, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy,C₁₋₄alkanoyl or SF₅; or corresponds to a group R₅; m₁, m₂, m₃, and m₄are 0;

m₅, m₆ and m₇ are each independently 0, 1 or 2 wherein the sum of m₅, m₆and m₇ is 1 or 2;

R₆ is C₁₋₆alkyl;R₇ is halogen, C₁₋₆alkyl or haloC₁₋₆alkyl;R₂ is hydrogen or C₁₋₄alkyl;n is 2 or 3;

X is S or —CH₂—;

R₃ is C₁₋₄alkyl;R₄ is hydrogen, or a phenyl group, a heterocyclyl group, a 5- or6-membered heteroaromatic group, or a 8- to 11-membered bicyclic group,any of which groups is optionally substituted by 1, 2, 3 or 4substituents selected from the group consisting of: halogen, cyano,C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy and C₁₋₄alkanoyl;R₅ is isoxazolyl, —CH₂—N-pyrrolyl, 1,1-dioxido-2-isothiazolidinyl,thienyl, thiazolyl, pyridyl or 2-pyrrolidinonyl, wherein each group isoptionally substituted by one or two substituents selected from:halogen, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy and C₁₋₄alkanoyl;with the proviso that when m5=m6=1, R₇ is not chlorine.

In a further embodiment, the present invention provides a compound offormula (ID) or a salt thereof:

wherein p, R₁, m₅, m₆, m₇, R₂, R₃, R₄, R₇ are defined as above forcompounds of formula (IC).

The term “5- or 6-membered ring containing one or two heteroatomsindependently selected from nitrogen and oxygen” refers to anon-saturated carbocyclic ring wherein one or two of the carbon atomsare replaced by nitrogen and/or oxygen. Examples include furanyl,pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, imidazolyl, pyrazolidinyl,isoxazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl.

The term “C₁₋₄alkyl” refers to an alkyl group having from one to fourcarbon atoms, in all isomeric forms, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. The term“n-C₁₋₄alkyl” refers to the unbranched alkyls as defined above.

The term “C₁₋₄alkoxy” refers to a straight chain or branched chainalkoxy (or “alkyloxy”) group having from one to four carbon atoms, suchas methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxyand tert-butoxy.

The term “C₁₋₄alkanoyl” refers to an alkanoyl group having from 1 to 4carbon atoms, such as methanoyl (or “formyl”), ethanoyl (or “acetyl”),propanoyl, isopropanoyl, butanoyl, isobutanoyl and sec-butanoyl.

The term “halogen” and its abbreviation “halo” refer to fluorine (F),chlorine (Cl), bromine (Br) or iodine (I). Where the term “halo” is usedbefore another group, it indicates that the group is substituted by one,two or three halogen atoms. For example, “haloC₁₋₄alkyl” refers togroups such as trifluoromethyl, bromoethyl, trifluoropropyl, and othergroups derived from C₁₋₄alkyl groups as defined above; and the term“haloC₁₋₄alkoxy” refers to groups such as trifluoromethoxy, bromoethoxy,trifluoropropoxy, and other groups derived from C₁₋₄alkoxy groups asdefined above.

The term “5- or 6-membered heteroaromatic group” refers to a monocyclic5- or 6-membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms,for example from 1 to 3 heteroatoms, selected from O, N and S. When thegroup contains 2-4 heteroatoms, one may be selected from O, N and S andthe remaining heteroatoms may be N. Examples of 5 and 6-memberedheteroaromatic groups include pyrrolyl, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, furyl, thienyl,thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazinyl, pyrimidinyland pyrazinyl.

The term “8- to 11-membered bicyclic group” refers to a bicyclic ringsystem containing a total of 8, 9, 10 or 11 carbon atoms, wherein 1, 2,3 or 4 or 5 of the carbon atoms are optionally replaced by a heteroatomindependently selected from O, S and N. The term includes bicyclicsystems wherein both rings are aromatic, as well as bicyclic ringsystems wherein one of the rings is partially or fully saturated.Examples of 8- to 11-membered bicyclic groups wherein both rings arearomatic include indenyl, naphthyl and azulenyl. Examples of 8- to11-membered bicyclic groups having 1, 2, 3, 4 or 5 heteroatoms, in whichboth rings are aromatic, include: 6H-thieno[2,3-b]pyrrolyl,imidazo[2,1-b][1,3]thiazolyl, imidazo[5,1-b][1,3]thiazolyl,[1,3]thiazolo[3,2-b][1,2,4]triazolyl, indolyl, isoindolyl, indazolyl,benzimidazolyl e.g. benzimidazol-2-yl, benzoxazolyl e.g.benzoxazol-2-yl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,benzothienyl, benzofuranyl, naphthridinyl, quinolyl, quinoxalinyl,quinazolinyl, cinnolinyl and isoquinolyl. Examples of 8- to 11-memberedbicyclic groups having 1, 2, 3, 4 or 5 heteroatoms, in which one of therings is partially or fully saturated includes dihydrobenzofuranyl,indanyl, tetrahydronaphthyl, indolinyl, isoindolinyl,tetrahydroisoquinolinyl, tetrahydroquinolyl, benzoxazinyl andbenzoazepinyl.

The term “heterocyclyl” refers to a 5 or 6-membered monocyclic or 8 to11-membered bicyclic group wherein 1, 2, 3, 4 or 5 of the carbon atomsare replaced by a heteroatom independently selected from O, S and N andwhich is partially or fully saturated. Examples of “heterocyclyl” whichare fully saturated 5 or 6-membered monocyclic rings includepyrrolidinyl, imidazolidinyl, pyrazolidinyl, isothiazolyl, thiazolyl,tetrahydrofuranyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, tetrahydrothienyl, dioxanyl, tetrahydro-2H-pyranyl anddithianyl. Examples of “heterocyclyl” groups which are partiallysaturated 5 or 6-membered monocyclic rings include oxazolinyl,isoaxazolinyl, imidazolinyl, pyrazolinyl, 1,2,3,6-tetrahydropyridyl and3,6-dihydro-2H-pyranyl. Examples of “heterocyclyl” groups which arefully saturated 8 to 11-membered bicyclic rings includedecahydroquinolinyl, octahydro-2H-1,4-benzoxazinyl andoctahydro-1H-cyclopenta-[b]pyridinyl. Examples of “heterocyclyl” groupswhich are partially saturated 8 to 11-membered bicyclic rings include2,3-dihydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl,1,2,3,4-tetrahydroisoquinolinyl and2,3,4,5-tetrahydro-1H-3-benzazepinyl.

Any of these groups may be attached to the rest of the molecule at anysuitable position.

As used herein, the term “salt” refers to any salt of a compoundaccording to the present invention prepared from an inorganic or organicacid or base, quaternary ammonium salts and internally formed salts.Physiologically acceptable salts are particularly suitable for medicalapplications because of their greater aqueous solubility relative to theparent compounds. Such salts must clearly have a physiologicallyacceptable anion or cation. Suitably physiologically acceptable salts ofthe compounds of the present invention include acid addition saltsformed with inorganic acids such as hydrochloric, hydrobromic,hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, andwith organic acids, such as tartaric, acetic, trifluoroacetic, citric,malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic,maleic, succinic, camphorsulfuric, isothionic, mucic, gentisic,isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic,anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic,alginic, galacturonic and arylsulfonic, for example benzenesulfonic andp-toluenesulfonic, acids; base addition salts formed with alkali metalsand alkaline earth metals and organic bases such asN,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumaine (N-methylglucamine), lysine and procaine;and internally formed salts. Salts having a non-physiologicallyacceptable anion or cation are within the scope of the invention asuseful intermediates for the preparation of physiologically acceptablesalts and/or for use in non-therapeutic, for example, in vitro,situations.

In one embodiment, p is 1 or 2.

In a further embodiment p is 1.

In another embodiment p is 0.

In one embodiment n is 2.

In one embodiment X is S.

In one embodiment, R₁ is haloC₁₋₆alkyl (such as CF₃).

In one embodiment, R₆ is methyl.

In another embodiment, R₇ is methyl.

In one embodiment, m₁, m₂, m₄, m₅, m₆ and m₇ are 0, m₃ is 1 and R₆ isC₁₋₆alkyl such as methyl.

In another embodiment, m₁, m₂, m₄, m₅, m₆ and m₃ are 0, m₇ is 1 and R₇is C₁₋₆alkyl such as methyl.

In still further embodiment, m₁, m₂, m₄, m₃, m₆ and m₇ are 0, m₅ is 1and R₇ is C₁₋₆alkyl such as methyl.

In one embodiment, R₂ is hydrogen.

In one embodiment, R₅ is a group selected from: isoxazolyl,2-pyrrolidinonyl, 1,1-dioxido-2-isothiazolidinyl which is optionallysubstituted by one or two substituents selected from: halogen, cyano,C₁₋₂alkyl (e.g. methyl), haloC₁₋₂alkyl (e.g. trifluoromethyl),C₁₋₂alkoxy (e.g. methoxy) and C₁₋₃alkanoyl (e.g. acetyl). For example,R₅ is isoxazolyl, 2-pyrrolidinonyl, —CH₂—N-pyrrolyl,1,1-dioxido-2-isothiazolidinyl, 2-thienyl, 2-pyridyl or 2-thiazolyl.

In one embodiment, R₄ is optionally substituted phenyl (e.g. phenyl,4-trifluoromethyl-phenyl, 3,4-difluorophenyl), an optionally substitutedbicyclic group such as quinolinyl (e.g. 2-methylquinoline,8-fluoro-2-methylquinoline), an optionally substituted pyranyl (e.g.4-tetrahydro-2H-pyranyl), an optionally substituted pyridinyl (e.g.3-methyl-2-pyridinyl, 2-methyl-3-pyridinyl, 3-pyridinyl,2-methyl-6-trifluoromethyl-3-pyridinyl), an optionally substitutedpyrazolyl (e.g. 5-chloro-1-methyl-1H-pyrazol-4-yl,1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl1,5-dimethyl-1H-pyrazoly-4-yl), an optionally substituted pyrimidyl(e.g. 5-pyrimidinyl), an optionally substituted pyridazinyl (e.g.4-pyridazinyl), an optionally substituted pyrazinyl (e.g.5-methyl-2-pyrazinyl), an optionally substituted furanyl (e.g.3-methyl-2-furanyl, 2,5-dimethyl-3-furanyl), an optionally substitutedthienyl (e.g. 5-chloro-2-thienyl), an optionally substituted oxazolyl(e.g. 4-methyl-1,3-oxazol-5-yl,2-methyl-5-trifluoromethyl-1,3-oxazol-4-yl), an optionally substitutedisoxazolyl (e.g. 3-methyl-5-isoxazolyl), an optionally substitutedthiazolyl (e.g. 2,4-dimethyl-1,3-thiazol-5-yl), an optionallysubstituted triazolyl (e.g. 1-methyl-1H-1,2,3-triazol-4-yl).

In another embodiment, R₄ is optionally substituted oxazolyl (such as4-methyl-1,3-oxazol-5-yl, 2-methyl-5-trifluoromethyl-1,3-oxazol-4-yl).

In one embodiment, R₃ is methyl.

Certain groups/substituents included in the present invention may bepresent as isomers. The present invention includes within its scope allsuch isomers, including racemates, enantiomers, tautomers and mixturesthereof. Certain of the substituted heteroaromatic groups included incompounds of formula (I) may exist in one or more tautomeric forms. Thepresent invention includes within its scope all such tautomeric forms,including mixtures.

It will be appreciated, in common with most biologically activemolecules that the level of biological activity may vary between theindividual stereoisomers of a given molecule. It is intended that thescope of the invention includes all individual stereoisomers(diastereoisomers and enantiomers) and all mixtures thereof, includingbut not limited to racemic mixtures, which demonstrate appropriatebiological activity with reference to the procedures described herein.

Because of the presence of the fused cyclopropane, compounds of formula(I) are believed to have a “cis” disposition with respect to the group(R₇)_(m7) and the phenyl group (both groups linked to the bicyclic ringsystem are on the same face of this bicyclic ring system). In anotherembodiment of the present invention, compounds of formula (I)′ areprovided which correspond to the compounds of formula (I) wherein thegroup (R₇)_(m7) and the phenyl group have a “cis” disposition,represented by the bold highlight of the bonds:

wherein p, R₁, m₁, m₂, m₃, m₄, m₅, m₆, m₇, R₆, R₇, n, X, R₂, R₃, R₄ aredefined as above for compounds of formula (I).

The two configurations of compounds of formula (I)′ are shown below:

In a further embodiment of the present invention compounds of formula(IA) are provided that correspond to stereochemical isomers of compoundsof formula (I)′, enriched in one configuration shown below

In a further embodiment of the present invention compounds of formula(IB) are provided that correspond to stereochemical isomers of compoundsof formula (I)′, enriched in one configuration shown below

In another embodiment of the present invention, compounds of formula(IC)′ are provided which correspond to the compounds of formula (IC)wherein the group (R₇)_(m7) and the phenyl group have a “cis”disposition, represented by the bold highlight of the bonds:

wherein p, R₁, m₁, m₂, m₃, m₄, m₅, m₆, m₇, R₆, R₇, n, X, R₂, R₃, R₄ aredefined as above for compounds of formula (I).

The two configurations of compounds of formula (IC)′ are shown below:

In a further embodiment of the present invention compounds of formula(IE) are provided that correspond to stereochemical isomers of compoundsof formula (IC)′, enriched in one configuration as shown below:

In a further embodiment of the present invention compounds of formula(IF) are provided that correspond to stereochemical isomers of compoundsof formula (IC)′, enriched in one configuration as shown below:

It is intended in the context of the present invention thatstereochemical isomers enriched in one configuration of formula (IA) or(IE) correspond in one embodiment to at least 90% e.e. In anotherembodiment the isomers correspond to at least 95% e.e. In anotherembodiment the isomers correspond to at least 99% e.e.

It is intended in the context of the present invention thatstereochemical isomers enriched in one configuration of formula (IB) or(IF) correspond in one embodiment to at least 90% e.e. In anotherembodiment the isomers correspond to at least 95% e.e. In anotherembodiment the isomers correspond to at least 99% e.e.

Certain of the compounds of the invention may form acid addition saltswith less than one equivalent, or one or more equivalents of the acid.The present invention includes within its scope all possiblestoichiometric and non-stoichiometric forms.

Pharmaceutical acceptable salts may also be prepared from other salts,including other pharmaceutically acceptable salts, of the compound offormula (I) using conventional methods.

Those skilled in the art of organic chemistry will appreciate that manyorganic compounds can form complexes with solvents in which they arereacted or from which they are precipitated or crystallized. Thesecomplexes are known as “solvates”. For example, a complex with water isknown as a “hydrate”. Solvates of the compound of the invention arewithin the scope of the invention. The compounds of formula (I) mayreadily be isolated in association with solvent molecules bycrystallisation or evaporation of an appropriate solvent to give thecorresponding solvates.

In addition, prodrugs are also included within the context of thisinvention. As used herein, the term “prodrug” means a compound which isconverted within the body, e.g. by hydrolysis in the blood, into itsactive form that has medical effects. Pharmaceutically acceptableprodrugs are described in T. Higuchi and V. Stella, Prodrugs as NovelDelivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, and in D. Fleisher,S. Ramon and H. Barbra “Improved oral drug delivery: solubilitylimitations overcome by the use of prodrugs”, Advanced Drug DeliveryReviews (1996) 19(2) 115-130, each of which are incorporated herein byreference.

Prodrugs are any covalently bonded carriers that release a compound ofstructure (I) in vivo when such prodrug is administered to a patient.Prodrugs are generally prepared by modifying functional groups in a waysuch that the modification is cleaved, either by routine manipulation orin vivo, yielding the parent compound. Prodrugs include, for example,compounds of this invention wherein hydroxy, amine or sulfhydryl groupsare bonded to any group that, when administered to a patient, cleaves toform the hydroxy, amine or sulfhydryl groups. Thus, representativeexamples of prodrugs include (but are not limited to) acetate, formateand benzoate derivatives of alcohol, sulfhydryl and amine functionalgroups of the compounds of structure (I). Further, in the case of acarboxylic acid (—COOH), esters may be employed, such as methyl esters,ethyl esters, and the like. Esters may be active in their own rightand/or be hydrolysable under in vivo conditions in the human body.Suitable pharmaceutically acceptable in vivo hydrolysable ester groupsinclude those which break down readily in the human body to leave theparent acid or its salt.

Furthermore, some of the crystalline forms of the compounds of structure(I) may exist as polymorphs, which are included in the presentinvention.

Those skilled in the art will appreciate that in the preparation of thecompound of the invention or a solvate thereof it may be necessaryand/or desirable to protect one or more sensitive groups in the moleculeto prevent undesirable side reactions. Suitable protecting groups foruse according to the present invention are well known to those skilledin the art and may be used in a conventional manner. See, for example,“Protective groups in organic synthesis” by T. W. Greene and P. G. M.Wuts (John Wiley & sons 1991) or “Protecting Groups” by P. J. Kocienski(Georg Thieme Verlag 1994). Examples of suitable amino protecting groupsinclude acyl type protecting groups (e.g. formyl, trifluoroacetyl,acetyl), aromatic urethane type protecting groups (e.g.benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic urethaneprotecting groups (e.g. 9-fluorenylmethoxycarbonyl (Fmoc),t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl)and alkyl type protecting groups (e.g. benzyl, trityl, chlorotrityl).Examples of suitable oxygen protecting groups may include for examplealkyl silyl groups, such as trimethylsilyl or tert-butyldimethylsilyl;alkyl ethers such as tetrahydropyranyl or tert-butyl; or esters such asacetate.

When a specific enantiomer of a compound of general formula (I) isrequired, this may be obtained for example by resolution of acorresponding enantiomeric mixture of a compound of formula (I) usingconventional methods. Thus the required enantiomer may be obtained fromthe racemic compound of formula (I) by use of chiral HPLC procedure.

The subject invention also includes isotopically-labelled compounds,which are identical to those recited in formula (I) and following, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention and salts thereof include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine,iodine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N 170, 180, ³¹P,³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵I.

Compounds of the present invention and salts of said compounds thatcontain the aforementioned isotopes and/or other isotopes of other atomsare within the scope of the present invention. Isotopically-labelledcompounds of the present invention, for example those into whichradioactive isotopes such as ³H, ¹⁴C are incorporated, are useful indrug and/or substrate tissue distribution assays. Tritiated, i.e., ³H,and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for theirease of preparation and detectability. ¹¹C and ¹⁸F isotopes areparticularly useful in PET (positron emission tomography), and ¹²⁵Iisotopes are particularly useful in SPECT (single photon emissioncomputerized tomography), all useful in brain imaging. Further,substitution with heavier isotopes such as deuterium, i.e., ²H, canafford certain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements and, hence, may be preferred in some circumstances.Isotopically labelled compounds of formula I and following of thisinvention can generally be prepared by carrying out the proceduresdisclosed in the Schemes and/or in the Examples below, by substituting areadily available isotopically labelled reagent for a non-isotopicallylabelled reagent.

In one embodiment of the present invention compounds are provided e amolecular weight of 800 or less. In another embodiment compounds areprovided having a molecular weight of 600 or less. Generally, andwithout being limited thereto, such compounds may have higher oralbioavailability, and sometimes higher solubility and/or brainpenetrancy. Molecular weight here refers to that of the unsolvated freebase compound, excluding any molecular weight contributed by additionsalts, solvent (e.g. water) molecules, prodrug molecular parts cleavedoff in vivo, etc.

In general, the compounds or salts of the invention should beinterpreted as excluding those compounds (if any) which are sochemically unstable, either per se or in water, that they are clearlyunsuitable for pharmaceutical use through all administration routes,whether oral, parenteral or otherwise. Such compounds are known to theskilled chemist. Prodrugs or compounds which are stable ex vivo andwhich are convertable in the mammalian (e.g. human) body to theinventive compounds are however included.

Example compounds of the present invention include

-   (1R,5S/1S,5R)-1-methyl-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-5-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane    and salts thereof.

The present invention also provides a process for preparing a compoundof formula (I) or a salt thereof as defined above, which processcomprises reacting a compound of formula (II):

wherein R₁, p and G are as defined for formula (I), with a compound offormula (III):

wherein R₂, R₃ and R₄ are as defined for formula (I) and L is a leavinggroup, and thereafter optionally:(i) removing any protecting group(s); and/or(ii) forming a salt; and/or(iii) converting a compound of formula (I) or a salt thereof to anothercompound of formula (I) or a salt thereof.

The above process may be performed using conventional methods for theformation of a tertiary amine. The leaving group L may be a halogen suchas chlorine. Alternatively L may be a sulfonyloxy group suchC₁₋₄alkylsulfonyloxy (e.g. methanesulfonyloxy), C₁₋₄alkylsulfonyloxy orhaloC₁₋₄alkylsulfonyloxy (e.g. trifluoromethanesulfonyloxy); orarylsulfonyloxy wherein aryl is optionally substituted phenyl, anoptionally substituted 5- or 6-membered heteroaromatic group, or anoptionally substituted bicyclic group, for example optionallysubstituted phenyl, wherein in each case the optional substituents areone or more C₁₋₂alkyl groups; e.g. para-toluenesulfonyloxy. When L is ahalogen the reaction may be carried out using a base such as potassiumcarbonate in the presence of a source of iodide such as sodium iodide ina solvent such as N,N-dimethylformamide at a suitable temperature, e.g.60° C.

Compounds of formula (II) may be prepared by methods well known in theart (e.g. J. Med. Chem. 1981, 24, 481-490). Interconversion of groups R₁may be effected by methodology well known in the art (e.g. demethylationof a methoxy group resulting in a hydroxy group using a suitable Lewisacidic reagent such as boron tribromide in an inert solvent such asdichloromethane).

One method for preparing a compound of formula (IIa), i.e. compounds offormula (II) wherein m₁, m₂, m₃, m₅ and m₄ are 0, m₆ is 1 and R₇ ismethyl is shown in scheme 1 below:

In the above scheme, Step (i) is a cyclopropanation reaction by means ofsulphur ylides (e.g. J.O.C., 1999, 64, 547). Step (ii) is a directexhaustive reduction using BH₃THF complex in THF, at reflux temperature,for 6-8 hours, followed by usual N-Boc protection with Boc anhydride inDCM. Step (iii) is the oxidation of the primary alcohol to aldehyde, eg.through the standard Swern procedure, then the reduction of the aldehydeto a methyl group (e.g. Synthesis, 2004, 308), followed by Boc removalwith TFA in DCM.

In another aspect of the present invention there is provided a syntheticprocess for the preparation of compounds of formula (IIb), i.e.compounds of general formula (II) wherein m₁, m₂, m₃, m₅, m₆ and m₄ are0, m₇ is 1 and R₇ is C₁₋₂ alkyl. This process comprises the followingsteps summarized in Scheme 2:

wherein:

-   -   step (a″) means bromuration of compound (VII) to give compound        (VIII);    -   step (b″) means reaction of compound (VIII) with a benzylic        amine (susceptible to afford benzylic cleavage in acidic        conditions) in to give imide (IX);    -   step (c″) means coupling of compound (IX) with an aryl boronic        acid to give compound (X);    -   step (d″) means removal of the benzylic protecting group of        compound (X) to give compound (XI);    -   step (e″) means cycloropanation of (XI) to provide bicyclic        imide (XII);    -   step (f″) means reduction of imide (XII) to give compounds of        formula (IIb).

Step (a′) may be effected using bromine in the presence of AlCl₃, andheating the mixture at high temperature, suitably 120° C.

Step (b″) may be performed heating compound (VIII) together with anappropriate benzylic amine (suitably 3,4-(dimethoxy)benzylamine or2,4-(dimethoxy)benzylamine) in the presence of AcONa and AcOH.

Step (c″) may be effected using conventional methods for the Suzukicoupling, e.g. using Pd(PPh₃)₂Cl₂ as the source of catalyticpalladium(0) in the presence of cesium fluoride, BnEt₃NCl and a genericarylboronic acid in an appropriate mixture of solvents, (such astoluene/H₂O1:1) at a suitable temperature (such as 90° C.).

Step (d″) may be performed through an appropriate method for acidiccleavage of benzylic protecting group, such as one of those reported in“Protective groups in organic synthesis” by T. W. Greene and P. G. M.Wuts (John Wiley & sons 1991) or “Protecting Groups” by P. J. Kocienski(Georg Thieme Verlag 1994). Suitably, if the benzylic group isrepresented by 3,4-(dimethoxy)benzyl, protection may be removed throughreaction of compound (X) with TFA and anisole in the presence ofsulforic acid.

Step (e″) consists of slow addition of a solution of purified compoundof formula (XI), or mixtures containing a compound of formula (XI),dissolved in a suitable solvent such as dimethylsulfoxide, to a solutionof trimethylsulfoxonium iodide in a suitable solvent such asdimethylsulfoxide and a suitable base, such as sodium hydride. This isfollowed by allowing time to react as appropriate and a suitable workup.

Step (f″) can be performed using a suitable reducing agent in acompatible solvent, such as borane in tetrahydrofuran or Red-Al® intoluene at an appropriate temperature, such as for example 65° C. in thecase of borane as the reducing agent. This is followed by a suitableworkup.

A compound of formula (III) may itself be prepared by reacting acompound of formula (XIII):

wherein R₃ and R₄ are as hereinbefore defined; with a compound offormula (XIV):

L(CHR₂)(CH₂)₂Y  (XIV)

wherein R₂ is defined as for formula (I) and L and Y are leaving groups,e.g., a bromine or chlorine.

Interconversion reactions between compounds of formula (I) and saltsthereof may be performed using methods well known in the art. Examplesinclude:

(i) converting one or more of R₁ from alkoxy (e.g. methoxy) to hydroxy,(ii) converting one or more of R₁ from hydroxy to sulfonyloxy, such asalkylsulfonyloxy or haloalkylsulfonyloxy, e.g. methanesulfonyloxy oralkylsulfonyloxy or trifluoro-methanesulfonyloxy,(iii) converting one or more of R₁ from halogen orperfluoroalkylsulfonyloxy to cyano; and optionally thereafter forming asalt of formula (I).

Compounds of formula (I) have been found to exhibit affinity fordopamine receptors, in particular the D₃ receptor, and are expected tobe useful in the treatment of disease states which require modulation ofsuch receptors, such as psychotic conditions. Such affinity is typicallycalculated from the IC₅₀ as the concentration of a compound necessary todisplace 50% of the radiolabeled ligand from the receptor, and isreported as a “K_(i)” value calculated by the following equation:

$K_{i} = \frac{{IC}_{50}}{1 + {L/K_{D}}}$

where L=radioligand and K_(D)=affinity of radioligand for receptor(Cheng and Prusoff, Biochem. Pharmacol. 22:3099, 1973).

In the context of the present invention pKi (corresponding to theantilogarithm of Ki) is used instead of Ki and the compounds of thepresent invention typically show pKi greater than 7. In one aspect thepresent invention provides compounds of formula (I) having a pKicomprised between 7 and 8. In another aspect the present inventionprovides compounds of formula (I) having a pKi comprised between 8 and9. In a further aspect the present invention provides compounds offormula (I) having a pKi greater than 9.

Many of the compounds of formula (I) have also been found to havegreater affinity for dopamine D₃ than for D₂ receptors. The therapeuticeffect of currently available antipsychotic agents (neuroleptics) isgenerally believed to be exerted via blockade of D₂ receptors; howeverthis mechanism is also thought to be responsible for undesirableextrapyramidal side effects (eps) associated with many neurolepticagents. It has been suggested that blockade of the recentlycharacterised dopamine D₃ receptor may give rise to beneficialantipsychotic activity without significant eps. (see for exampleSokoloff et al, Nature, 1990; 347: 146-151; and Schwartz et al, ClinicalNeuropharmacology, Vol 16, No. 4, 295-314, 1993). In one embodimentcompounds of the present invention are provided which have higher (e.g.≧10× or ≧100× higher) affinity for dopamine D₃ than dopamine D₂receptors (such affinity can be measured using standard methodology forexample using cloned dopamine receptors—see herein). Said compounds maysuitably be used as selective modulators of D₃ receptors.

From the localisation of D₃ receptors, it could also be envisaged thatthe compounds could also have utility for the treatment of asubstance-related disorder where it has been suggested that D₃ receptorsare involved (e.g. see Levant, 1997, Pharmacol. Rev., 49, 231-252).Examples of such substance abuse include alcohol, cocaine, heroin andnicotine abuse. Compounds of formula (I) may be used for treatment ofall aspects of drug dependency including drug intake, relapse todrug-seeking behaviour following abstinence and withdrawal symptoms fromdrugs of abuse such as alcohol, cocaine, opiates, nicotine,benzodiazepines and inhibition of tolerance induced by opioids. Inaddition, compounds of formula (I) and salts and solvates thereof may beused to reduce craving and therefore will be useful in the treatment ofdrug craving. Drug craving can be defined as the incentive motivation toself-administer a psychoactive substance that was previously consumed.Three main factors are involved in the development and maintenance ofdrug craving: (1) Dysphoric states during drug withdrawal can functionas a negative reinforcer leading to craving; (2) Environmental stimuliassociated with drug effects can become progressively more powerful(sensitization) in controlling drug seeking or craving, and (3) Acognition (memory) of the ability of drugs to promote pleasurableeffects and to alleviate a dysphoric state during withdrawal. Cravingmay account for the difficulty that individuals have in giving up drugsof abuse and therefore contributes significantly to the development andmaintenance of drug dependence.

The compounds of formula (I) are of potential use as antipsychoticagents for example in the treatment of schizophrenia, schizo-affectivedisorders, psychotic depression, mania, paranoid and delusionaldisorders. Furthermore, they could have utility as adjunct therapy inParkinsons Disease, particularly with compounds such as L-DOPA andpossibly dopaminergic agonists, to reduce the side effects experiencedwith these treatments on long term use (e.g. see Schwartz et al., BrainRes. Reviews, 1998, 26, 236-242). Other conditions which may be treatedby the compounds include dyskinetic disorders such as Parkinson'sdisease, neuroleptic-induced parkinsonism and tardive dyskinesias;depression; anxiety, cognitive impairment including memory disorderssuch as Alzheimers disease, eating disorders, sexual dysfunction, sleepdisorders, emesis, movement disorders, obsessive-compulsive disorders,amnesia, aggression, autism, vertigo, dementia, circadian rhythmdisorders and gastric motility disorders e.g. IBS.

A wide range of psychiatric and neuropsychiatric disorders appear to berelated to Obsessive-Compulsive Disorder, and form a family of relateddisorders referred to as obsessive-compulsive (OC) spectrum disorders.The compounds of formula (I) may be used for the treatment of anobsessive-compulsive spectrum disorder, including somatoform disorderssuch as body dysmorphic disorder and hyperchondriasis, bulimia nervosa,anorexia nervosa, binge eating, paraphilia and nonparaphilic sexualaddictions, Sydeham's chorea, torticollis, autism, compulsive hoarding,and movement disorders, including Tourette's syndrome. As used herein,the phrase “obsessive-compulsive spectrum disorder” is intended toinclude Obsessive-Compulsive Disorder.

The compounds of formula (I) are also useful for the treatment ofpremature ejaculation.

Within the context of the present invention, the terms describing theindications used herein are classified in the Diagnostic and StatisticalManual of Mental Disorders, 4th Edition, published by the AmericanPsychiatric Association (DSM-IV) and/or the International Classificationof Diseases, 10th Edition (ICD-10). The various subtypes of thedisorders mentioned herein are contemplated as part of the presentinvention. Numbers in brackets after the listed diseases below refer tothe classification code in DSM-IV.

Within the context of the present invention, the term “substance-relateddisorder” includes:—

Substance-related disorders including Substance Use Disorders such asSubstance Dependence, Substance Craving and Substance Abuse;Substance-Induced Disorders such as Substance Intoxication, SubstanceWithdrawal, Substance-Induced Delirium, Substance-Induced PersistingDementia, Substance-Induced Persisting Amnestic Disorder,Substance-induced Psychotic Disorder, Substance-Induced Mood Disorder,Substance-Induced Anxiety Disorder, Substance-induced SexualDysfunction, Substance-Induced Sleep Disorder and HallucinogenPersisting Perception Disorder (Flashbacks); Alcohol-Related Disorderssuch as Alcohol Dependence (303.90), Alcohol Abuse (305.00), AlcoholIntoxication (303.00), Alcohol Withdrawal (291.81), Alcohol IntoxicationDelirium, Alcohol Withdrawal Delirium, Alcohol-Induced PersistingDementia, Alcohol-Induced Persisting Amnestic Disorder, Alcohol-InducedPsychotic Disorder, Alcohol-Induced Mood Disorder, Alcohol-inducedAnxiety Disorder, Alcohol-Induced Sexual Dysfunction, Alcohol-InducedSleep Disorder and Alcohol-Related Disorder Not Otherwise Specified(291.9); Amphetamine (or Amphetamine-Like)-Related Disorders such asAmphetamine Dependence (304.40), Amphetamine Abuse (305.70), AmphetamineIntoxication (292.89), Amphetamine Withdrawal (292.0), AmphetamineIntoxication Delirium, Amphetamine Induced Psychotic Disorder,Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder,Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced SleepDisorder and Amphetamine-Related Disorder Not Otherwise Specified(292.9); Caffeine Related Disorders such as Caffeine Intoxication(305.90), Caffeine-Induced Anxiety Disorder, Caffeine-Induced SleepDisorder and Caffeine-Related Disorder Not Otherwise Specified (292.9);Cannabis-Related Disorders such as Cannabis Dependence (304.30),Cannabis Abuse (305.20), Cannabis Intoxication (292.89), CannabisIntoxication Delirium, Cannabis-Induced Psychotic Disorder,Cannabis-Induced Anxiety Disorder and Cannabis-Related Disorder NotOtherwise Specified (292.9); Cocaine-Related Disorders such as CocaineDependence (304.20), Cocaine Abuse (305.60), Cocaine Intoxication(292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium,Cocaine-Induced Psychotic Disorder, Cocaine-induced Mood Disorder,Cocaine-Induced Anxiety Disorder, Cocaine-Induced Sexual Dysfunction,Cocaine-Induced Sleep Disorder and Cocaine-Related Disorder NotOtherwise Specified (292.9); Hallucinogen-Related Disorders such asHallucinogen Dependence (304.50), Hallucinogen Abuse (305.30),Hallucinogen Intoxication (292.89), Hallucinogen Persisting PerceptionDisorder (Flashbacks) (292.89), Hallucinogen Intoxication Delirium,Hallucinogen-induced Psychotic Disorder, Hallucinogen-Induced MoodDisorder, Hallucinogen-induced Anxiety Disorder and Hallucinogen-RelatedDisorder Not Otherwise Specified (292.9); Inhalant-Related Disorderssuch as Inhalant Dependence (304.60), Inhalant Abuse (305.90), InhalantIntoxication (292.89), Inhalant Intoxication Delirium, Inhalant-inducedPersisting Dementia, Inhalant-Induced Psychotic Disorder,Inhalant-Induced Mood Disorder, Inhalant-Induced Anxiety Disorder andInhalant-Related Disorder Not Otherwise Specified (292.9);Nicotine-Related Disorders such as Nicotine Dependence (305.1), NicotineWithdrawal (292.0) and Nicotine-Related Disorder Not Otherwise Specified(292.9); Opioid-Related Disorders such as Opioid Dependence (304.00),Opioid Abuse (305.50), Opioid Intoxication (292.89), Opioid Withdrawal(292.0), Opioid Intoxication Delirium, Opioid-Induced PsychoticDisorder, Opioid-Induced Mood Disorder, Opioid-Induced SexualDysfunction, Opioid-Induced Sleep Disorder and Opioid-Related DisorderNot Otherwise Specified (292.9); Phencyclidine (orPhencyclidine-Like)-Related Disorders such as Phencyclidine Dependence(304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxication(292.89), Phencyclidine Intoxication Delirium, Phencyclidine-InducedPsychotic Disorder, Phencyclidine-Induced Mood Disorder,Phencyclidine-Induced Anxiety Disorder and Phencyclidine-RelatedDisorder Not Otherwise Specified (292.9); Sedative-, Hypnotic-, orAnxiolytic-Related Disorders such as Sedative, Hypnotic, or AnxiolyticDependence (304.10), Sedative, Hypnotic, or Anxiolytic Abuse (305.40),Sedative, Hypnotic, or Anxiolytic Intoxication (292.89), Sedative,Hypnotic, or Anxiolytic Withdrawal (292.0), Sedative, Hypnotic, orAnxiolytic Intoxication Delirium, Sedative, Hypnotic, or AnxiolyticWithdrawal Delirium, Sedative-, Hypnotic-, or Anxiolytic-PersistingDementia, Sedative-, Hypnotic-, or Anxiolytic-Persisting AmnesticDisorder, Sedative-, Hypnotic-, or Anxiolytic-Induced PsychoticDisorder, Sedative-, Hypnotic-, or Anxiolytic-Induced Mood Disorder,Sedative-, Hypnotic-, or Anxiolytic-Induced Anxiety Disorder Sedative-,Hypnotic-, or Anxiolytic-Induced Sexual Dysfunction, Sedative-,Hypnotic-, or Anxiolytic-Induced Sleep Disorder and Sedative-,Hypnotic-, or Anxiolytic-Related Disorder Not Otherwise Specified(292.9); Polysubstance-Related Disorder such as Polysubstance Dependence(304.80); and Other (or Unknown)

Substance-Related Disorders such as Anabolic Steroids, Nitrate Inhalantsand Nitrous Oxide.

Within the context of the present invention, the term “psychoticdisorder” includes:—

Schizophrenia including the subtypes Paranoid Type (295.30),Disorganised Type (295.10), Catatonic Type (295.20), UndifferentiatedType (295.90) and Residual Type (295.60); Schizophreniform Disorder(295.40); Schizoaffective Disorder (295.70) including the subtypesBipolar Type and Depressive Type; Delusional Disorder (297.1) includingthe subtypes Erotomanic Type, Grandiose Type, Jealous Type, PersecutoryType, Somatic Type, Mixed Type and Unspecified Type; Brief PsychoticDisorder (298.8); Shared Psychotic Disorder (297.3); Psychotic DisorderDue to a General Medical Condition including the subtypes With Delusionsand With Hallucinations; Substance-Induced Psychotic Disorder includingthe subtypes With Delusions (293.81) and With Hallucinations (293.82);and Psychotic Disorder Not Otherwise Specified (298.9).

In a further aspect therefore the present invention provides a method oftreating a condition for which modulation [especiallyinhibition/antagonism (which may also translate into inverse agonism inconstitutively active receptor systems)] of dopamine receptors(especially dopamine D₃ receptors) is beneficial, which comprisesadministering to a mammal (e.g. human) in need thereof an effectiveamount of a compound of formula (I) or a pharmaceutically (i.ephysiologically) acceptable salt thereof. In one embodiment, thecondition is a substance-related disorder, a psychotic disorder, anobsessive compulsive spectrum disorder or premature ejaculation.

The invention also provides the use of a compound of formula (I) or asalt thereof in the manufacture of a medicament for the treatment of acondition in a mammal for which modulation [especiallyinhibition/antagonism (which may also translate into inverse agonism inconstitutively active receptor systems)] of dopamine receptors(especially dopamine D₃ receptors) is beneficial.

The invention also provides a compound of formula (I) or a salt thereoffor use in the treatment of a condition in a mammal for which modulation[especially inhibition/antagonism (which may also translate into inverseagonism in constitutively active receptor systems)] of dopaminereceptors (especially dopamine D₃ receptors) is beneficial.

In one embodiment, the compounds of the present invention are used inthe treatment of a substance-related disorder, a psychotic disorder, anobsessive compulsive spectrum disorder or premature ejaculation.

Thus, a still further aspect the invention provides a method of treatinga psychotic disorder (e.g. schizophrenia), a substance-related disorder,an obsessive compulsive spectrum disorder or premature ejaculation,which comprises administering to a mammal (e.g. human) in need thereofan effective amount of a compound of formula (I) as herein defined or asalt thereof.

Also provided is the use of a compound of formula (I) or a salt thereofin the manufacture of a medicament for the treatment of a a psychoticdisorder (e.g. schizophrenia), a substance-related disorder, anobsessive compulsive spectrum disorder or premature ejaculation.

Also provided is a compound of formula (I) or a salt thereof for use inthe treatment of a psychotic disorder (e.g. schizophrenia), asubstance-related disorder, an obsessive compulsive spectrum disorder orpremature ejaculation.

Also provided is a compound of formula (I) or a salt thereof for use asa therapeutic substance in a mammal, e.g. for use in the treatment ofany of the conditions described herein.

“Treatment” includes prophylaxis, where this is appropriate for therelevant condition(s).

For use in medicine, the compounds of the present invention are usuallyadministered as a standard pharmaceutical composition. The presentinvention therefore provides in a further aspect a pharmaceuticalcomposition comprising a compound of formula (I) or a pharmaceutically(i.e physiologically) acceptable salt thereof and a pharmaceutically(i.e physiologically) acceptable carrier. The pharmaceutical compositioncan be for use in the treatment of any of the conditions describedherein.

The compounds of formula (I) may be administered by any convenientmethod, for example by oral, parenteral (e.g. intravenous), buccal,sublingual, nasal, rectal or transdermal administration and thepharmaceutical compositions adapted accordingly.

The compounds of formula (I) and their salts which are active when givenorally can be formulated as liquids or solids, for example syrups,suspensions or emulsions, tablets, capsules and lozenges.

A liquid formulation will generally consist of a suspension or solutionof the compound or salt in a suitable liquid carrier(s) for example anaqueous solvent such as water, ethanol or glycerine, or a non-aqueoussolvent, such as polyethylene glycol or an oil. The formulation may alsocontain a suspending agent, preservative, flavouring or colouring agent.

A composition in the form of a tablet can be prepared using any suitablepharmaceutical carrier(s) routinely used for preparing solidformulations. Examples of such carriers include magnesium stearate,starch, lactose, sucrose and cellulose. A composition in the form of acapsule can be prepared using routine encapsulation procedures. Forexample, pellets containing the active ingredient can be prepared usingstandard carriers and then filled into a hard gelatin capsule;alternatively, a dispersion or suspension can be prepared using anysuitable pharmaceutical carrier(s), for example aqueous gums,celluloses, silicates or oils and the dispersion or suspension thenfilled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension ofthe compound or salt in a sterile aqueous carrier or parenterallyacceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone,lecithin, arachis oil or sesame oil. Alternatively, the solution can belyophilised and then reconstituted with a suitable solvent just prior toadministration.

Compositions for nasal administration may conveniently be formulated asaerosols, drops, gels and powders. Aerosol formulations typicallycomprise a solution or fine suspension of the active substance in apharmaceutically acceptable aqueous or non-aqueous solvent and areusually presented in single or multidose quantities in sterile form in asealed container, which can take the form of a cartridge or refill foruse with an atomising device. Alternatively the sealed container may bea unitary dispensing device such as a single dose nasal inhaler or anaerosol dispenser fitted with a metering valve which is intended fordisposal once the contents of the container have been exhausted. Wherethe dosage form comprises an aerosol dispenser, it will contain apropellant which can be a compressed gas such as compressed air or anorganic propellant such as a fluoro-chlorohydrocarbon. The aerosoldosage forms can also take the form of a pump-atomiser.

Compositions suitable for buccal or sublingual administration includetablets, lozenges and pastilles, wherein the active ingredient isformulated with a carrier such as sugar and acacia, tragacanth, orgelatin and glycerin.

Compositions for rectal administration are conveniently in the form ofsuppositories containing a conventional suppository base such as cocoabutter. Compositions suitable for transdermal administration includeointments, gels and patches.

In one embodiment, the composition is in unit dose form such as atablet, capsule or ampoule.

Each dosage unit for oral administration contains for example from 1 to250 mg (and for parenteral administration contains for example from 0.1to 25 mg) of a compound of the formula (I) or a salt thereof calculatedas the free base.

The pharmaceutically acceptable compounds of the invention will normallybe administered in a daily dosage regimen (for an adult patient) of, forexample, an oral dose of between 1 mg and 500 mg, for example between 10mg and 400 mg, e.g. between 10 and 250 mg or an intravenous,subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, forexample between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of thecompound of the formula (I) or a salt thereof calculated as the freebase, the compound being administered 1 to 4 times per day. Suitably thecompounds will be administered for a period of continuous therapy, forexample for a week or more.

Biological Test Methods

Functional potency and intrinsic activity of compounds of this inventioncan be measured by the following GTPγS scintillation proximity assay(GTPγS-SPA). Cells used in the study are Chinese Hamster Ovary (CHO)Cells.

Cell Line CHO_D2 CHO_D3

Compounds may be tested according to two alternative protocols:

a) Cell membranes are prepared as follows. Cell pellets are resuspendedin 10 volumes of 50 mM HEPES, 1 mM EDTA pH 7.4, using KOH. On the daythe following proteases are added to the buffer just prior to giving thehomogenisation buffer.2.12×10⁻⁶ M Leupeptin (Sigma L2884)−5000× stock=5 mg/ml in buffer25 ug/ml Bacitracin (Sigma B0125)−1000× stock=25 mg/ml in buffer1 mM PMSF−100× stock=17 mg/ml in 100% ethanol2×10⁻⁶M Pepstatin A−1000× stock=2 mM in 100% DMSO

The cells are homogenised by 2×15 second bursts in a 1 litre GlassWaring blender in a class two biohazard cabinet. The resultingsuspension is spun at 500 g for 20 mins (Beckman T21 centrifuge: 1550rpm). The supernatant is withdrawn with a 25 ml pipette, aliquotted intopre-chilled centrifuge tubes and spun at 48,000 g to pellet membranefragments (Beckman T1270: 23,000 rpm for 30 mins). The final 48,000 gpellet is resuspended in Homogenisation Buffer, (4× the volume of theoriginal cell pellet). The 48,000 g pellet is resuspended by vortexingfor 5 seconds and homogenized in a dounce homogenizer 10-15 stokes. Theprep is distributed into appropriate sized aliquots, (200-1000 ul), inpolypropylene tubes and store at −80° C. Protein content in the membranepreparations is evaluated with the Bradford protein assay.

The final top concentration of test drug is 3 uM in the assay and 11points serial dilution curves 1:4 in 100% DMSO are carried out using aBiomek FX. The test drug at 1% total assay volume (TAV) is added to asolid, white, 384 well assay plate. 50% TAV of precoupled (for 90 minsat 4° C.) membranes, 5 μg/well, and Wheatgerm Agglutinin PolystyreneScintillation Proximity Assay beads (RPNQ0260, Amersham), 0.25 mg/well,in 20 mM HEPES pH 7.4, 100 mM NaCl, 10 mM MgCl₂, 60 μg/ml saponin and 30μM GDP is added. The third addition was a 20% TAV addition of eitherbuffer, (agonist format) or EC₈₀ final assay concentration of agonist,Quinelorane, prepared in assay buffer (antagonist format). The assay wasstarted by the addition of 29% TAV of GTPγ[³⁵S] 0.38 nM final (37MBq/ml, 1160Ci/mmol, Amersham). After all additions assay plates arespun down for 1 min at 1,000 rpm. Assay plates are counted on a Viewlux,613/55 filter, for 5 min., between 2-6 hours after the final addition.

The effect of the test drug over the basal generates EC₅₀ value by aniterative least squares curve fitting programme, expressed in the tableas pEC₅₀ (i.e. −logEC₅₀). The ratio between the maximal effect of thetest drug and the maximal effect of full agonist, Quinelorane, generatesthe Intrinsic Activity (IA) value (i.e. IA=1 full agonist, IA<1 partialagonist). fpKi values of test drug are calculated from the IC₅₀generated by “antagonist format” experiment, using Cheng & Prusoffequation: fKi=IC₅₀/1+([A]/EC₅₀) where: [A] is the concentration of theagonist 5-HT in the assay and EC₅₀ is the 5-HT EC₅₀ value obtained inthe same experiment. fpKi is defined as −logfKi.

b) Cell membranes are prepared as follows. Cell pellets are resuspendedin 10 volumes of 50 mM HEPES, 1 mM EDTA pH 7.4, using KOH. On the daythe following proteases are added to the buffer just prior to giving thehomogenisation buffer.

10⁻⁴ M Leupeptin (Sigma L2884)

25 ug/ml Bacitracin (Sigma B0125)1 mM PMSF−100× stock=17 mg/ml in 100% ethanol2×10⁻⁶M Pepstatin A−500× stock=1 mM in 100% ethanol

The cells were homgenised within a glass waring blender for 2×15 secs in200 mls of 50 mM HEPES+10−4M leupeptin+25 ug/ml bacitracin+1 mM EDTA+1mM PMSF+2 uM Pepstatin A, (the latter 2 reagents added as fresh ×100 and×500 stocks respectively in ethanol). The blender was plunged into icefor 5 mins after the first burst and 10-40 mins after the final burst toallow foam to dissipate. The material was then spun at 500 g for 20 minsand the supernatant spun for 36 mins at 48,000 g. The pellet wasresuspended in the same buffer as above but without PMSF and PepstatinA. The material was then forced through a 0.6 mm needle, made up to therequired volume, (usually ×4 the volume of the original cell pellet),aliquoted and stored frozen at −80 deg C.

The final top concentration of test drug is 3 uM in the assay and 11points serial dilution curves 1:4 in 100% DMSO are carried out using aBiomek FX. The test drug at 1% total assay volume (TAV) is added to asolid, white, 384 well assay plate. 50% TAV of precoupled (for 60 minsat RT) membranes, 5 μg/well, and Wheatgerm Agglutinin PolystyreneScintillation Proximity Assay beads (RPNQ0260, Amersham), 0.25 mg/well,in 20 mM HEPES pH 7.4, 100 mM NaCl, 10 mM MgCl₂, 60 μg/ml saponin and30□M GDP is added. The third addition was a 20% TAV addition of eitherbuffer, (agonist format) or EC80 final assay concentration of agonist,Quinelorane, prepared in assay buffer (antagonist format). The assay wasstarted by the addition of 29% TAV of GTP[35S] 0.38 nM final (37 MBq/ml,1160Ci/mmol, Amersham). After all additions assay plates are spun downfor 1 min at 1,000 rpm. Assay plates are counted on a Viewlux, 613/55filter, for 5 min., between 3-6 hours after the final addition.

The effect of the test drug over the basal generates EC50 value by aniterative least squares curve fitting programme, expressed in the tableas pEC50 (i.e.−logEC50). The ratio between the maximal effect of thetest drug and the maximal effect of full agonist, Quinelorane, generatesthe Intrinsic Activity (IA) value (i.e. IA=1 full agonist, IA<1 partialagonist). fpKi values of test drug are calculated from the IC₅₀generated by “antagonist format” experiment, using Cheng & Prusoffequation: fKi=IC50/1+([A]/EC50) where: [A] is the concentration of theagonist Quinelorane in the assay and EC50 is the Quinelorane EC50 valueobtained in the same experiment. fpKi is defined as −logfKi.

The compounds of the invention listed above have pKi values within therange of 7.0-10.5 at the dopamine D3 receptor. pKi results are onlyestimated to be accurate to about ±0.3-0.5.

The compounds of the invention listed above have a selectivity over D2greater than 30.

EXAMPLES

The invention is further illustrated by the following non-limitingexamples.

All temperatures refer to ° C. Infrared spectra were measured on a FT-IRinstrument. Compounds were analysed by direct infusion of the sampledissolved in acetonitrile into a mass spectra operated in positiveelectro spray (ES+) ionisation mode. Proton Magnetic Resonance (¹H-NMR)spectra were recorded at 400 MHz, chemical shifts are reported in ppmdownfield (d) from Me₄Si, used as internal standard, and are assigned assinglets (s), broad singlets (bs), doublets (d), doublets of doublets(dd), triplets (t), quartets (q) or multiplets (m).

Column chromathography was carried out over silica gel (Merck AGDarmstaadt, Germany). The following abbreviations are used in the text:HOBt=1-hydroxybenzotriazole EtOAc=ethyl acetate, Et₂O=dietyl ether,DMF=N,N′-dimethylformamide, MeOH=methanol, SCX=strong cation exchanger,Tlc refers to thin layer chromatography on silica plates, and driedrefers to a solution dried over anhydrous sodium sulphate, r.t. (RT)refers to room temperature, Rt=retention time, DMSO=dimethyl sulfoxide;DCM=dichloromethane; AcOH=acetic acid; AcONa=sodium acetate; AcOEt=ethylacetate.

Preparation 1: 3-bromo-4-methyl-2,5-furandione (P1)

A mixture of 3-methyl-2,5-furandione (citraconic anhydride, 1 g), AlBr₃(26 mg) and Br₂ (0.46 mL) was heated at 120° C. overnight. Ethyl acetatewas then added and the organic phase was washed with HCl 0.1% and thenwith brine. The organic phase was dried and concentrated in vacuo togive the crude product (1.680 g) that was used without furtherpurification.

NMR (¹H, CDCl₃): δ 2.18 (s, 3H)

Preparation 2:11-{[3,4-bis(methyloxy)phenyl]methyl}-3-bromo-4-methyl-1H-pyrrole-2,5-dione(P2)

A mixture of 3-bromo-4-methyl-2,5-furandione (P1, 1 g),1-[3,4-bis(methyloxy)phenyl]methanamine (874 mg), and AcOH (20 mL) washeated at 100° C. overnight. The solution was then concentrated invacuo. AcOH (20 mL) and AcONa (315 mg) were added to the crude productand the mixture was refluxed for 2 hours. Water was then added and theaqueous phase was extracted with DMC. The organic phase was dried andevaporated in vacuo. The crude product was purified by flashchromatography eluting with cyclohexane/AcOEt from 9/1 to 8/2 to givethe title compound (1.364 g).

NMR (¹H, CDCl₃) δ 7.75 (dd, 4H), 7.03 (m, 2H), 6.80 (d, 1H), 4.70 (s,2H), 3.89 (s, 3H), 3.87 (s, 3H), 2.25 (s, 3H).

Preparation 3:1-{[3,4-bis(methyloxy)phenyl]methyl}-3-methyl-4-[4-(trifluoromethyl)phenyl]-1H-pyrrole-2,5-dione(P3)

A solution of11-{[3,4-bis(methyloxy)phenyl]methyl}-3-bromo-4-methyl-1H-pyrrole-2,5-dione(P2, 1 g), [4-(trifluoromethyl)phenyl]boronic acid (1.117 g),Pd(PPh₃)₂Cl₂ (206 mg), cesium fluoride (1.206 g) andbenzyltriethylammonium chloride (67 mg), in toluene/H₂O 1:1 (30 mL) washeated at 90° C. overnight. The solution was then concentrated in vacuo,dichloromethane was added and the organic phase washed with NH₄Cl(aqueous saturated solution), dried on sodium sulphate and evaporated invacuo. The crude product was purified by flash chromatography elutingwith cyclohexane/ethyl acetate from 7/3 to 4/6 to give the titlecompound (1.183 g).

NMR (¹H, CDCl₃) δ 7.75 (dd, 4H), 7.05 (m, 2H), 6.80 (d, 1H), 4.69 (s,2H), 3.89 (s, 3H), 3.87 (s, 3H), 2.25 (s, 3H).

Preparation 4:3-methyl-4-[4-(trifluoromethyl)phenyl]-1H-pyrrole-2,5-dione (P4)

A solution of1-{[3,4-bis(methyloxy)phenyl]methyl}-3-methyl-4-[4-(trifluoromethyl)phenyl]-1H-pyrrole-2,5-dione(P3, 100 mg), anisole (107 μL), TFA (4 mL) and H₂SO₄ (catalytic amount)was heated at 90° C. overnight. The solution was then concentrated invacuo, dichloromethane was added and the organic phase was washed withNaHCO₃ (aqueous saturated solution), dried on sodium sulphate andevaporated in vacuo. The crude was purified by flash chromatographyeluting with cyclohexane/ethyl acetate 8/2 to give the title compound(50 mg).

NMR (1H, CDCl₃) δ 7.78 (dd, 4H), 7.35 (bs, 1H), 2.25 (s, 3H). MS (m/z):254[M]⁻

Preparation 5:(1R,5S/1S,5R)-1-methyl-5-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane-2,4-dione(P5)

Sodium hydride 60% (15 mg) was added in small portions to a stirredsolution of trimethylsulfoxonium iodide (83 mg) in DMSO (anhydrous, 1ml) and the resulting mixture was allowed to stir at room temperaturefor 1.5 h. 3-Methyl-4-[4-(trifluoromethyl)phenyl]-1H-pyrrole-2,5-dione(P4, 48 mg) dissolved in DMSO (anhydrous, 1 ml) was then added dropwiseand the resulting mixture was allowed to stir at room temperature for 20minutes. Temperature was then reduced to 0° C. and NH₄Cl (aqueoussaturated solution) was slowly added, followed by Et₂O. After separationof the two phases, the aqueous layer was repeatedly extracted with Et₂O.Combined organic layers were washed with brine and then dried overNa₂SO₄ and evaporated in vacuo. The crude was purified by flashchromatography eluting with cyclohexane/ethyl acetate from 8/2 to 7/3 togive the title compound (28 mg).

NMR (¹H, CDCl₃) δ 7.7 (d, 2H), 7.48 (m, 3H), 2.15 (d, 1H), 1.85 (d, 1H),1.25 (s, 3H). MS (m/z): 268[M]⁻

Preparation 6:(1R,5S/1S,5R)-1-methyl-5-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane(P6)

To a solution of borane (1M in tetrahydrofuran, 208 μl) was added(1R,5S/1S,5R)-1-methyl-5-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane-2,4-dione(P5, 28 mg) dissolved in tetrahydrofuran (anhydrous, 1 mL) and then thesolution was reflux for 6 hours. The mixture was cooled to 0° C. andaqueous hydrochloric acid (6 M, 0.5 mL) was cautiously added monitoringgas evolution and then the mixture was reflux for 3 h. Sodium hydroxide(5 M solution) was added until pH 5 had been reached. The aqueous layerwas extracted with DCM. The organic phase was dried and evaporated invacuo. The residue was charged onto an SCX column and eluted with MeOHfollowed by MeOH/NH₃ 0.25 M. The methanole/ammonia fractions wereconcentrated under reduced pressure to give of the title compound (15mg).

NMR (¹H, CDCl₃) δ 7.58 (d, 2H), 7.39 (d, 2H), 3.27 (bs, 2H), 3.15 (d,1H), 3.01 (d, 1H), 0.99 (m, 4H), 0.92 (d, 1H). MS (m/z): 242.2 [MH]⁺.

Preparation 7:3-[(3-chloropropyl)thio]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(P7)

Ethyl-2-chloroacetoacetate (1 wt; 1 eq., 1000 g) was aged with formamide(0.68 vol; ca. 2.8 eq.) and the resulting solution was heated to 120° C.After 5 hours the mixture was allowed to cool to room temperature andallowed to age under nitrogen over night. The mixture was treated withNaOH (3 M, 6 vol, reaction moderately exothermic) and stirred at roomtemperature for 4 hours. Ethyl acetate (6 vol) was added and the phasesallowed to separate. The organic layer was discarded while the aqueouswas acidified with conc. (32%) aqueous HCl to pH 2 (ca. 2.0 vol). Aprecipitate started to form. The suspension was treated with AcOEt (8vol) and vigorously stirred until the bulk of the precipitate haddissolved. The aqueous phase was further extracted with AcOEt twice (6vol each) and the combined organic layers distilled to low volume (againa suspension was observed at low volume). Fresh AcOEt (8 vol) was addedand the mixture evaporated to dryness. The collected solid was placed inthe oven at 40° C. over night under reduced pressure to give4-methyl-1,3-oxazole-5-carboxylic acid (498 g, 64.5%).

This material (498 g, 1 wt) was dissolved in dry tetrahydrofuran (5vol), under nitrogen, cooled to 0° C. DCC (1.62 wt, 1 eq) was addedportionwise followed by HOBt (1.07 wt, 1 eq). The mixture was warmed to25±2° C. and stirred for 30 min. 4-Methyl-3-thiosemicarbazide (0.83 wt,1 eq) was then added and the mixture further stirred for 2 h at 25±2° C.The mixture was filtered and the cake was washed with freshtetrahydrofuran (1 vol) and dried on the filter for a few hours. Thecake was suspended in 1 M aqueous NaOH (13 vol) and heated to 70° C. for30 min. After this time, the mixture was cooled to 25±2° C. and a solidwas removed by filtration. The cake was washed with 1 M aqueous NaOH (10vol). The combined mother liquors were cooled to 0° C. and acidified toca. pH with HCl (aqueous, 16%; NOTE: keep temperature while adding HClbelow +10° C.). The suspended product was isolated by filtration washingwith water (2×3 vol). The cake was dried at 40° C. for 18 h in highvacuum to obtain4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione(respectively a tautomeric form thereof; 290 g, 37%).

NaOEt (21% solution in EtOH, 2.08 vol, 1.1 eq) was added to EtOH (20vol) under nitrogen atmosphere.4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione(respectively a tautomeric form thereof; 290 g, 1 wt) was added in oneportion and the resulting mixture stirred at 25±2° C. until a clearsolution was obtained. Then 1-bromo-3-chloropropane (0.54 vol, 1.1 eq)was added and the solution stirred at 40° C. for 24 h then cooled to 25°C. After filtration water (20 vol) was added and the ethanolic phase wasremoved by vacuum distillation (internal temperature ˜40° C.). Themixture was extracted with EtOAc (41 vol). The aqueous layer was removedand the organic phase was evaporated to dryness. Dichloromethane (4 vol)was added. The organic solution is purified through a short silica gelcolumn (18 wt of silica), eluting with EtOAc (200 vol) to give the titlecompound as a foam (267.64 g).

NMR (¹H, CDCl₃): δ 7.90 (s, 1H), 3.70 (s, 5H), 3.40 (t, 2H), 2.52 (s,3H), 2.30 (m, 2H).

Example 1(1R,5S/1S,5R)-1-methyl-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-5-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexanehydrochloride

A mixture of(1R,5S/1S,5R)-1-methyl-5-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane(P6, 13 mg),3-[(3-chloropropyl)thio]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(P7, 29 mg), K₂CO₃ (9 mg) and NaI (10 mg) in DMF (0.5 mL) was heated at60° C. for 24 h. DCM was added to the reaction mixture and the organiclayer was washed with saturated aqueous solution of NH₄Cl, dried overNa₂SO₄ and the solvent evaporated under reduced pressure. The crudeproduct was purified by flash chromatography (eluting withcychloexane/ethyl acetate from 3/7 to 2/8) to give 7 mg of the free baseof the title compound. To a solution of this material in dichloromethaneHCl (1M in Et₂O, 15 μL) was added, the solvent evaporated under vacuumto give 4 mg of the title compound as a white slightly hygroscopicsolid.

NMR (¹H, CDCl₃): 7.95 (m, 1H), 7.57 (d, 2H), 7.39 (d, 2H), 3.73 (m, 3H),3.36 (m, 2H), 3.23 (m, 2H), 2.69 (m, 3H), 2.55 (m, 3H), 2.41 (m, 1H),2.02 (m, 2H), 1.51 (m, 1H), 0.97 (m, 3H), 0.78 (m, 1H). MS (m/z): 478.23[MH]⁺.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The application of which this description and claims forms part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described herein. They may take the form ofproduct, composition, process, or use claims and may include, by way ofexample and without limitation, the following claims:

1-19. (canceled)
 20. A compound of formula (IC) or a salt thereof:

wherein: p is 0 to 4; R₁ is independently selected from a groupconsisting of: halogen, hydroxy, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl,C₁₋₄alkoxy, haloC₁₋₄alkoxy, and C₁₋₄alkanoyl or SF₅; or is R₅; m₁, m₂,m₃, and m₄ are 0; m₅, m₆ and m₇ are each independently 0, 1 or 2 whereinthe sum of m₅, m₆ and m₇ is 1 or 2; R₆ is C₁₋₆alkyl; R₇ is halogen,C₁₋₆alkyl or haloC₁₋₆alkyl; R₂ is hydrogen or C₁₋₄alkyl; n is 2 or 3; Xis S or —CH₂—; R₃ is C₁₋₄alkyl; R₄ is hydrogen, phenyl, a heterocyclylgroup, a 5- or 6-membered heteroaromatic group, or a 8- to 11-memberedbicyclic group, any of which groups is optionally substituted by 1, 2, 3or 4 substituents selected from the group consisting of halogen, cyano,C₁₋₁₄alkyl, haloC₁₋₁₄alkyl, C₁₋₁₄alkoxy and C₁₋₄alkanoyl; R₅ isisoxazolyl, —CH₂—N-pyrrolyl, 1,1-dioxido-2-isothiazolidinyl, thienyl,thiazolyl, pyridyl or 2-pyrrolidinonyl, wherein each group is optionallysubstituted by one or two substituents selected from the groupconsisting of halogen, cyano, C₁₋₄alkyl, haloC₁₋₁₄alkyl, C₁₋₁₄alkoxy andC₁₋₄alkanoyl; with the proviso that when m₅=m₆=1, R₇ is not chlorine.21. A compound as claimed in claim 20, wherein p is 1 or
 2. 22. Acompound as claimed in claim 20, wherein R₁ is haloC₁₋₆alkyl.
 23. Acompound as claimed claim 20, wherein R₇ is methyl.
 24. A compound asclaimed in claim 20, wherein m₁, m₂, m₄, m₅, m₆ and m₃ are 0, m₇ is 1and R₇ is C₁₋₆alkyl.
 25. A compound as claimed in claim 20, wherein m₁,m₂, m₄, m₃, m₆ and m₇ are 0, m₅ is 1 and R₇ is C₁₋₆alkyl.
 26. A compoundas claimed in claim 20, wherein R₂ is hydrogen.
 27. A compound asclaimed in claim 20, wherein R₄ is optionally substituted oxazolyl. 28.A compound as claimed in claim 20, wherein R₃ is methyl.
 29. A compoundas claimed in claim 20, which is(1R,5S/1S,5R)-1-methyl-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-5-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexaneor a salt thereof.
 30. A compound as claimed in claim 20, having aformula (IC)′ or a salt thereof:

wherein p, R₁, m₁, m₂, m₃, m₄, m₅, m₆, m₇, R₆, R₇, n, X, R₂, R₃, R₄ aredefined in claim
 20. 31. A process for preparing a compound of formula(IC) as defined in claim 20 or a salt thereof, which process comprisesreacting a compound of formula (II):

wherein R₁, p and G are as defined for formula (IC) in claim 20, with acompound of formula (III):

wherein R₂, R₃ and R₄ are as defined for formula (IC) in claim 20 and Lis a leaving group, and thereafter optionally: (i) removing anyprotecting group(s); and/or (ii) forming a salt; and/or (iii) convertinga compound of formula (I) or a salt thereof to another compound offormula (I) or a salt thereof.
 32. A method of treating a condition forwhich modulation of dopamine D₃ receptors is beneficial, which comprisesadministering to a mammal (e.g. human) in need thereof an effectiveamount of a compound of claim
 20. 33. A method as claimed in claim 32,wherein the condition is a substance-related disorder is schizophreniaor premature ejaculation.
 34. A pharmaceutical composition comprising acompound as claimed in claim 20 and a pharmaceutically acceptablecarrier.